WO2018007919A1 - Nouveau procédé pour des intermédiaires de sacubitril précoces - Google Patents

Nouveau procédé pour des intermédiaires de sacubitril précoces Download PDF

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WO2018007919A1
WO2018007919A1 PCT/IB2017/053971 IB2017053971W WO2018007919A1 WO 2018007919 A1 WO2018007919 A1 WO 2018007919A1 IB 2017053971 W IB2017053971 W IB 2017053971W WO 2018007919 A1 WO2018007919 A1 WO 2018007919A1
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formula
salt
compound
hydrogen
group
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PCT/IB2017/053971
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Florian Karl KLEINBECK-RINIKER
Tobias Kapferer
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Novartis Ag
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Priority to EP17743393.5A priority Critical patent/EP3481799A1/fr
Priority to CN201780041934.1A priority patent/CN109415308B/zh
Priority to US16/314,933 priority patent/US20190256454A1/en
Priority to JP2018568727A priority patent/JP6944473B2/ja
Publication of WO2018007919A1 publication Critical patent/WO2018007919A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
    • C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/18—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B51/00—Introduction of protecting groups or activating groups, not provided for in the preceding groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines

Definitions

  • the present invention relates to a new chemical synthesis route for intermediates useful for the preparation of neprilysin (NEP) inhibitors and their prodrugs, in particular for the NEP inhibitor prodrug sacubitril.
  • NEP neprilysin
  • NEP inhibitor prodrug sacubitril (/V-(3-carboxyl-1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)- 4-amino-(2f?)-methyl butanoic acid ethyl ester; lUPAC name 4- ⁇ [(1 S,3f?)-1 -([1 ,1 '-biphenyl]-4- ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino ⁇ -4-oxobutanoic acid, also known as AHU377) is represented by the following formula (A)
  • Sacubitril together with valsartan a known angiotensin receptor blocker (ARB), forms a sodium salt hydrate complex, known as LCZ696, comprising the anionic forms of sacubitril and valsartan, sodium cations and water molecules in the molar ratio of 1 :1 :3:2.5, respectively (ratio of 6:6:18:15 in the asymmetric unit cell of the solid state crystal) (WO 2007/056546), and which is schematically present in formula (B).
  • ARB angiotensin receptor blocker
  • LCZ696 acts as angiotensin receptor neprilysin inhibitor (ARNI) and is therefore useful particularly in the treatment of hypertension or chronic heart failure. Its utility has been confirmed by clinical trials, e.g. in the landmark PARADIGM-HF trial.
  • ARNI angiotensin receptor neprilysin inhibitor
  • WO 2013/026773, WO 2014/032627 and WO 2015/024991 deal with novel synthesis methods to provide the precursor compound , in particular
  • the invention relates to novel intermediates and process steps and processes for the manufacture of a compound of formula (II), especially (ll-a) represented below, and its further use in the manufacture of sacubitril.
  • the present invention relates to the novel compound of formula (II), or a salt thereof
  • R1 is hydrogen or a nitrogen protecting group.
  • the present invention relates to a process for preparing such a novel compound of formula (II), or a salt thereof
  • R1 is hydrogen or a nitrogen protecting group
  • R1 is hydrogen or a nitrogen protecting group
  • R2 is a CO-activating group, with a biphenylic compound.
  • the invention relates to processes using the novel compound of formula (II).
  • One aspect relates to a process for producing a free or preferably nitrogen-protected amino alcohol compound according to formula (I), or a salt thereof,
  • R1 is hydrogen or a nitrogen protecting group
  • R1 is hydrogen or a nitrogen protecting group
  • the compound of formula (II) represents a key intermediate for the synthesis of NEP inhibitors or prodrugs thereof, or salts thereof. Accordingly, in a fourth aspect, the present invention relates to the use of the novel compound of formula (II), or a salt thereof
  • R1 is hydrogen or a nitrogen protecting group
  • R1 is hydrogen or C Ce-alkyl, preferably ethyl
  • the NEP-inhibitor /V-(3-carboxy-1 -oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid, or a salt thereof or the NEP-inhibitor pro-drug /V-(3-carboxy-1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester (known in the art as AHU377 or sacubitril) or a salt thereof.
  • the invention relates to any one or more of the novel compounds, processes and catalysts represented in the claims, which are incorporated here by reference.
  • the invention also relates to any sequential combination of the process steps described above and below.
  • the synthesis route is suitable for industrial scale processing.
  • the synthesis route is economically and environmentally favorable.
  • the compounds of formula (I) and (XVI) which are intermediates desired for the synthesis of sacubitril can be produced with high yield and high stereoselectivity.
  • chiral refers to molecules which have the property of non-superimposability on their mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • ⁇ w > " on a C-sp 3 represents a covalent bond, wherein the stereochemistry of the bond is not defined.
  • >A " on a C-sp 3 comprises an (S) configuration as well as an (R) configuration of the respective chiral centre.
  • mixtures e.g. mixtures of enantiomers such as racemates, are also encompassed by the present invention .
  • the term /wv" on a C-sp 2 represents a covalent bond, wherein the stereochemistry or the geometry of the bond is not defined. This means that the term " > ⁇ " on a C-sp 2 comprises a (Z) configuration as well as a (£) configuration of the respective double bond. Furthermore, mixtures, e.g. , mixtures of double bond isomers are also encompassed by the present invention .
  • the term " indicates a C-sp 3 -C-sp 3 bond or a C-sp 2 -C-sp 2 bond.
  • the compounds of the present invention can possess one or more asymmetric centers.
  • the preferred absolute configurations are as indicated herein specifically. However, any possible pure enantiomer, pure diastereoisomer, or mixtures thereof, e.g., mixtures of enantiomers, such as racemates, are encompassed by the present invention.
  • Stereoisomeric, especially enantiomeric, purity, is where mentioned referring to all diastereomers of the compound taken together (100%). It is determined by chiral chromatography (examples include HPLC, uPLC and GC) or NMR (with addition of chiral entities and or metals).
  • pro-drug represents in particular compounds which are transformed in vivo to the parent compound, for example, by hydrolysis in blood, for example as described in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", volume 14 of the ACS Symposium Series; Edward B. Roche, editor, “Bioreversible Carriers in Drug Design", American Pharmaceutical Association and Pergamon Press, 1987; H Bundgaard, editor, “Design of Prodrugs”, Elsevier, 1985; Judkins et al. Synthetic Communications 1996, 26, 4351 -4367, and "The Organic Chemistry of Drug Design and Drug Action", second edition, R. B. Silverman (particularly chapter 8, pages 497-557), Elsevier Academic Press, 2004.
  • Pro-drugs therefore include drugs having a functional group which has been transformed into a reversible derivative thereof. Typically, such prodrugs are transformed to the active drug by hydrolysis. As examples may be mentioned the following:
  • Carboxylic acid Esters including e.g. alkyl esters
  • Alcohol Esters including e.g. sulfates and phosphates as
  • Amine Amides carbamates, imines, enamines,
  • Pro-drugs also include compounds convertible to the active drug by an oxidative or reductive reaction. As examples may be mentioned:
  • NEP inhibitor describes a compound which inhibits the activity of the enzyme neutral endopeptidase (NEP, EC 3.4.24.1 1).
  • NEP-inhibitor or “NEP-inhibitor prodrug” relates to the substances as such or to salts thereof, preferably pharmaceutically acceptable salts thereof. Examples are sodium, potassium, magnesium, calcium or ammonium salts. Calcium salts are preferred.
  • NEP inhibitor prodrug /V-(3-carboxy-1 -oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester optionally may be further reacted to obtain the active NEP inhibitor /V-(3-carboxy-1 -oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid, either in vitro or in vivo.
  • AlkyI is defined as a radical or part of a radical as a straight or branch (one or, if desired and possible, more times) carbon chain, and is especially C Cy-alkyl, preferably C Ce-alkyl, more preferably Crd-alkyl.
  • C -C 7 - defines a moiety with up to and including maximally 7, especially up to and including maximally 6 and 4 respectively, carbon atoms, said moiety being branched (one or more times) or straight-chained and bound via a terminal or a non-terminal carbon.
  • Cycloalkyl is, for example, C 3 -C 7 -cycloalkyl and is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cyclopentyl and cyclohexyl are preferred.
  • Alkoxy is, for example, CrCy-alkoxy and is, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, fe/ -butyloxy and also includes corresponding pentyloxy, hexyloxy and heptyloxy radicals.
  • C ⁇ C ⁇ alkoxy is preferred.
  • C 2 -C 5 -Alkanoyl is preferred, especially acetyl.
  • Halo or halogen is preferably fluoro, chloro, bromo or iodo, most preferably, chloro, bromo, or iodo.
  • Halo-alkyl is, for example, halo-CrCy-alkyl and is in particular halo-Ci-C 4 -alkyl, such as trifluoromethyl, 1 ,1 ,2-trifluoro-2-chloroethyl or chloromethyl.
  • Preferred halo-C C 7 -alkyl is trifluoromethyl.
  • Alkenyl may be linear or branched alkyl containing a double bond and comprising preferably 2 to 12 carbon atoms, 2 to 10 carbon atoms being especially preferred. Particularly preferred is a linear C 2 _C 7 -alkenyl, more preferably C 2 _C 4 -alkenyl.
  • alkyl groups are ethyl and the isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octacyl and eicosyl, each of which containing a double bond. Especially preferred is allyl.
  • Alkylene is a bivalent radical derived from and is especially C 2 -C 7 -alkylene or C 2 - C 7 -alkylene and, optionally, can be interrupted by one or more, e.g. up to three oxygen, NR14 or sulfur, wherein R14 is alkyl, each of which can be unsubstituted or substituted, by one or more substituents independently selected from for example, C Cy-alkyl, C C 7 - alkoxy-C Cy-alkyl or C Cy-alkoxy.
  • Alkenylene is a bivalent radical derived from C 2 . 7 -alkenyl and can be interrupted by one or more, e.g. up to three oxygen, NR14 or sulfur, wherein R14 is alkyl, and is unsubstituted or substituted by one or more, e.g. up to three substitutents, preferably independently selected from the substituents mentioned above for alkylene.
  • Aryl being a radical or part of a radical is, for example C 6 -io-aryl, and is preferably a mono- or polycyclic, especially monocyclic, bicyclic or tricyclic aryl moiety with 6 to 10 carbon atoms, such as phenyl, naphthyl or fluorenyl preferably phenyl, and which can be unsubstituted or substituted, by one or more substituents, independently selected from, e.g. C Cy-alkyl, C Cy-alkoxy-C Cy-alkyl or C C 7 -alkoxy.
  • arylalkyi refers to aryl-C Cy-alkyl, wherein aryl is as defined herein and is for example benzyl.
  • carboxyl refers to -C0 2 H.
  • Aryloxy refers to an aryl-O- wherein aryl is as defined above.
  • heterocyclyl is an aromatic ring system, it is also referred to as heteroaryl.
  • Heterocyclyl is preferably imizazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyranyl, diazionyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, azepanyl, oxepanyl, thiepanyl, indolyl, isoindoly, quinolinyl, isoquinolinyl, benzazepinyl, carbazolyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolinidyl, thiazolidy, dioxolanyl, dithiolanyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, tetrazolyl, piperidinyl, piperaz
  • heterocyclylalkyl the heterocyclyl is preferably as just defined and is attached to an alkyl as defined for alkyl.
  • alkyl as defined for alkyl.
  • Examples are imidazolylmethyl, pyridylmethyl or piperidinylmethyl.
  • Sulfonyl is (unsubstituted or substituted) C Cy-alkylsulfonyl, such as methylsulfonyl, (unsubstituted or substituted) phenyl- or naphthyl-C Cy-alkylsulfonyl, such as phenylmethanesulfonyl, or (unsubstituted or substituted) phenyl- or naphthyl-sulfonyl; wherein if more than one substituent is present, e.g.
  • the substituents are selected independently from cyano, halo, halo-C Cy-alkyl, halo-C Cy- alkyloxy- and C Cy-alkyloxy.
  • C Cy-alkylsulfonyl such as methylsulfonyl
  • phenyl- or naphthyh-CrCy-alkylsulfonyl such as phenylmethanesulfonyl.
  • Sulfenyl is (unsubstituted or substituted) or (unsubstituted or substituted) C 6 . 10 -arylsulfenyl, wherein if more than one substituent is present, e.g. one to four substitutents, the substituents are selected independently from nitro, halo, halo-C Cy- alkyl and C Cy-alkyloxy.
  • Imide refers to a (unsubstituted or substituted) functional group consisting of two acyl groups bound to nitrogen, preferably a cyclic group derived from dicarboxylic acids. Especially preferred is succinimidyl derived from succinic acid or phthalimidyl derived from phthalic acid.
  • the imidyl group may be substituted by one or more substituents independently selected from for example, Ci-C 7 -alkyl, CrCy-alkoxy-CrCy-alkyl, CrC 7 - alkoxy or halo.
  • Silyl refers to a group according to the formula -SiR1 1 R12R13, wherein R1 1 , R12 and R13 are, independently of each other, Ci-C 7 -alkyl, C 6 -C 10 -aryl or phenyl-C ⁇ . C 4 -alkyl.
  • R1 1 , R12 and R13 are methyl, ethyl, isopropyl, fe/ -butyl, phenyl or phenyl-C ⁇ -alkyl.
  • Salts are especially pharmaceutically acceptable salts or generally salts of any of the intermediates mentioned herein, except if salts are excluded for chemical reasons the skilled person will readily understand. They can be formed where salt forming groups, such as basic or acidic groups, are present that can exist in dissociated form at least partially, e.g. in a pH range from 4 to 10 in aqueous solutions, or can be isolated especially in solid, especially crystalline, form.
  • salt forming groups such as basic or acidic groups
  • Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds or any of the intermediates mentioned herein with a basic nitrogen atom (e.g. imino or amino), especially the pharmaceutically acceptable salts.
  • Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, lactic acid, fumaric acid, succinic acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, benzoic acid, methane- or ethane-sulfonic acid, ethane-1 ,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1 ,5- naphthalene-disulfonic acid, /V-cyclohexylsulfamic acid, /V-methyl-, /V-ethyl- or /V-propyl- sulfamic acid, or other organic protonic acids, such as ascorbic acid.
  • salts may also be formed with bases, e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri(2-hydroxyethyl)amine, or heterocyclic bases, for example /V-ethyl- piperidine or /V,/V-dimethylpiperazine.
  • bases e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri(2-hydroxyethyl)amine, or heterocyclic bases, for example /V-ethyl- piperidine or /V,/V-dimethyl
  • any of the intermediates mentioned herein may also form internal salts.
  • pharmaceutically unacceptable salts for example picrates or perchlorates.
  • any reference to "compounds", “starting materials” and “intermediates” hereinbefore and hereinafter is to be understood as referring also to one or more salts thereof or a mixture of a corresponding free compound, intermediate or starting material and one or more salts thereof, each of which is intended to include also any solvate or salt of any one or more of these, as appropriate and expedient and if not explicitly mentioned otherwise.
  • Different crystal forms may be obtainable and then are also included.
  • nitrogen protecting group comprises any group which is capable of reversibly protecting a nitrogen functionality, preferably an amine and/or amide functionality.
  • the nitrogen protecting group is an amine protecting group and/or an amide protecting group.
  • Suitable nitrogen protecting groups are conventionally used e.g. in peptide chemistry and are described e.g. in the relevant chapters of standard reference works such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in P. G. M. Wuts and T. W. Greene, “Greene's Protective Groups in Organic Synthesis', fourth edition, Wiley, New Jersey, 2007, and “The Peptides”; volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981 , and “Methoden der organischen Chemie” (Methods of Organic Chemistry), Houben Weyl, fourth edition, volume 15/1, Georg Thieme Verlag, Stuttgart 1974.
  • Preferred nitrogen protecting groups generally comprise: unsubstituted or substituted C ⁇ Ce- alkyl, preferably C ⁇ C ⁇ alkyl, more preferably C 1 -C 2 -alkyl, most preferably C alkyl, unsubstituted or substituted C -alkenyl, wherein each C Ce-alkyl and C -alkenyl is optionally mono-, di- or tri-substituted by trialkylsilyl-CrCy-alkoxy (e.g.
  • cycloalkyi aryl, preferably phenyl, or a heterocyclic group, preferably pyrrolidinyl, wherein the cycloalkyi group, the aryl ring or the heterocyclic group is unsubstituted or substituted by one or more, e.g. two or three residues, e.g. selected from the group consisting of C C 7 - alkyl, hydroxy, C 2 -C 8 -alkanoyl-oxy, halogen, nitro, cyano, and CF 3 ; aryl-C C 2 -alkoxycarbonyl (preferably phenyl-C C ⁇ alkoxycarbonyl e.g.
  • benzyloxycarbonyl C ⁇ o- alkenyloxycarbonyl; C -alkylcarbonyl (e.g. acetyl or pivaloyl); C 6 -io-arylcarbonyl; Ci -6 - alkoxycarbonyl (e.g. fe/ -butoxycarbonyl); C ⁇ o-aryl-C ⁇ -alkoxycarbonyl; allyl or cinnamyl; sulfonyl or sulfenyl; a succinimidyl group, substituted silyl, e.g. triarylsilyl or trialkylsilyl (e.g. triethylsilyl).
  • nitrogen protecting groups are acetyl, benzyl, cumyl, benzhydryl, trityl, benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbony (Fmoc), benzyloxymethyl (BOM), pivaloyl-oxy-methyl (POM), trichloroethxoycarbonyl (Troc), 1 -adamantyloxycarbonyl (Adoc), allyl, allyloxycarbonyl, trimethylsilyl, fe/ -butyl-dimethylsilyl (TBDMS), triethylsilyl (TES), triisopropylsilyl (TIPS), trimethylsilyethoxymethyl (SEM), fe/ -butoxycarbonyl (BOC), fe/ -butyl, 1 -methyl-1 ,1 -dimethylbenzyl, (phenyl)methylbenzene, pyrridinyl and pi
  • nitrogen protecting groups are acetyl, benzyl, benzyloxycarbonyl (Cbz), triethylsilyl (TES), trimethylsilyethoxymethyl (SEM), fe/ -butoxycarbonyl (BOC), pyrrolidinylmethyl and pivaloyl.
  • nitrogen protecting groups are, pivaloyl, pyrrolidinylmethyl, t- butoxycarbonyl, benzyl and silyl groups, particularly silyl groups according to the formula SiR1 1 R12R13 group, wherein R1 1 , R12 and R13 are, independently of each other, C C 7 - alkyl, C 6 -C 10 -aryl or phenyl-Ci-C 4 -alkyl.
  • Preferred examples for R1 1 , R12 and R13 are methyl, ethyl, isopropyl, t-butyl and phenyl.
  • nitrogen protecting groups are fe/ -butoxycarbonyl (BOC), benzoyl, styryl, 1 -butenyl, benzyl, p-methoxybenzyl (PMB) and pyrrolidinylmethyl, in particular pivaloyl and fe/ -butoxycarbonyl (BOC).
  • C Ce-alkyl which is unsubstituted or mono-, di- or tri-substituted by tri-CrCe-alkylsilylCrCy- alkoxy, C 6 -C 10 -aryl, or a heterocyclic group being a mono-, bi- or tricyclic ring system with 5 to 14 ring atoms and 1 to 4 heteroatoms independently selected from N, O, S, S(O) or S(0) 2 , wherein the aryl ring or the heterocyclic group is unsubstituted or substituted by one, two or three residues, selected from the group consisting of C Cy-alkyl, hydroxyl, C Cy- alkoxy, C 2 -C 8 -alkanoyl-oxy, halogen, nitro, cyano, and CF 3 ;
  • each silyl group is a SiR1 1 R12R13 group, wherein R1 1 , R12 and R13 are, independently of each other, C Cy-alkyl, C 6 -C 10 -aryl or phenyl-d.C ⁇ alkyl.
  • nitrogen protecting group comprises any group which is capable of reversibly protecting an amino functionality.
  • the removal usually can be carried out by using known methods, e.g. as described in the references cited above.
  • the nitrogen protecting group is removed by using acidic or basic conditions.
  • acidic conditions are hydrochloric acid, trifluoroacetic acid, sulphuric acid.
  • basic conditions are lithium hydroxide, sodium ethoxide. Nucleophiles such as sodium borohydride can be used.
  • N- benzyl as amino protecting group it can be removed by hydrogenation or by the use of some suitable oxidizing agents, e.g. eerie ammonium nitrate (CAN) or 2,3-dichloro-5,6- dicyano-p-benzoquinone (DDQ).
  • the present invention relates to a compound of formula (II), or a salt thereof
  • R1 is hydrogen or a nitrogen protecting group.
  • the compound is of formula (ll-a), or a salt thereof
  • R1 is hydrogen or a nitrogen protecting group.
  • R1 is hydrogen
  • R1 is a nitrogen protecting group selected from C Ce-alkyl, which is unsubstituted or mono-, di- or tri-substituted by tri-C Ce-alkylsilylC Cy-alkoxy, C 6 -C 10 -aryl, or a heterocyclic group being a mono-, bi- or tricyclic ring system with 5 to 14 ring atoms and 1 to 4 heteroatoms independently selected from N, O, S, S(O) or S(0) 2 , wherein the aryl ring or the heterocyclic group is unsubstituted or substituted by one, two or three residues, selected from the group consisting of C Cy-alkyl, hydroxyl, C Cy-alkoxy, C 2 -C 8 -alkanoyl-oxy, halogen, nitro, cyano, and CF 3 ;
  • each silyl group is a SiR1 1 R12R13 group, wherein R1 1 , R12 and R13 are, independently of each other, C Cy-alkyl, C 6 -C 10 -aryl or phenyl-C ⁇ C ⁇ alkyl.
  • R1 is C Cy-alkoxycarbonyl, especially fe/f-butoxycarbonyl (BOC).
  • the present invention relates to a process for preparing such compound of formula (II), or a salt thereof
  • R1 is hydrogen or a nitrogen protecting group
  • R1 is hydrogen or a nitrogen protecting group
  • R2 is a CO-activating group, with a biphenylic compound.
  • the present invention relates to a process for preparing compound of formula (ll-a), or a salt thereof
  • R1 is hydrogen or a nitrogen protecting group
  • R1 (lll-a) wherein R1 is hydrogen or a nitrogen protecting group, and R2 is a CO-activating group, with a biphenylic compound.
  • R2 is a CO-activating group.
  • a suitable CO-activating group generally is any group, which can act as a leaving group. Examples of groups which can act as a CO-activating group are -NR 2 , -OR, -SR or halogen, wherein R is hydrogen or (optionally substituted) alkyl or (optionally substituted) aryl.
  • CO-activating group R2 in compounds of formula (III) or (lll-a):
  • R2 can be an amino group, in particular, -NR12R13, wherein R12 and R13 are
  • R12 is alkyl (eg methyl) and R13 is selected from the group consisting of alkoxy (eg. methoxy or ethoxy), aryloxy (eg. phenyloxy) and arylalkoxy (eg, benzyloxy); or
  • alkenylene for example piperidinyl, morpholinyl, 1 -alkylpiperazinyl (for example 1 - methylpiperazinyl), 2-, 3-, 4-alkylpiperidinyl, 1 ,2,3,6-tetrahydropyridinyl, pyrrolidinyl or imidazolyl; or
  • R12 is alkyl (eg. methyl) and R13 is -X-R14, wherein X is S and R14 is alkyl (eg. methyl or ethyl), aryl (eg. phenyl) or arylalkyi (eg. benzyl); or
  • R12 is alkyl (eg. methyl) and R13 is— NRaRb, wherein Ra and Rb are independently selected from alkyl (eg. methyl or ethyl), aryl (eg. phenyl) or arylalkyi (eg. benzyl).
  • R2 is a dialkylated amino group, which can be cyclic (e.g. morpholinyl or imidazolyl) or acyclic (eg. dimethylamino).
  • Cyclic amino groups preferably comprise a 5-member or 6- member ring, with or without additional substitution, in particular substitution refers to one or more substituents selected from the group consisting of halo, alkyl, alkoxy, aryl, aryloxy, arylalkyi and arylalkoxy.
  • alkylaryl amino groups e.g. phenylmethylamino
  • diaryl amino groups e.g. diphenylamino
  • Weinreb derivatives i.e.
  • derivatives of methylmethoxyamine in particular -NR12R13, wherein R12 is methyl or methoxy and R13 is independently selected from alkyl, alkoxy, aryl, aryloxy, arylalkyi or arylalkoxy .
  • R12 is methyl or methoxy
  • R13 is independently selected from alkyl, alkoxy, aryl, aryloxy, arylalkyi or arylalkoxy .
  • amino groups possessing an alkyl/aryl group and a coordinating group e.g. alkoxy, alkylthio.
  • R2 can be a group having the formula -X-R, wherein X is O or S and R is alkyl or aryl.
  • R4 can be a group having the formula -O-CO-R, wherein R is alkyl or aryl.
  • R2 can be a halo, preferably chloro.
  • R2 can be -0-R15 wherein R15 is -NR12R13, as defined above, or R15 is
  • the CO-activating group is selected from ⁇ /, ⁇ -dimethylhydroxylamino
  • N(Me)OMe dimethylamino, morpholinyl, imidazolyl, -O-methyl, -O-ethyl, chloro, bromo, pivaloyi and acetyl, preferably ⁇ /, ⁇ -dimethylhydroxylamino (N(Me)OMe) (Weinreb amide) or morpholinyl.
  • the residue R1 is preferably a nitrogen protecting group, as defined above, or alternatively hydrogen. If the CO-activating group is chosen from the above group (C) in formula (III), the residue R1 is preferably hydrogen.
  • the biphenylic compound can be activated.
  • a suitable method for the activation is the preparation of an organometallic complex comprising a biphenyl ligand.
  • Preferred activated biphenylic compounds are biphenyl magnesium halide or
  • Suitable halides generally are chloride, bromide and iodide, wherein bromide is especially preferred.
  • the Grignard reagent is either prepared according to appropriate reaction conditions well-known in the art or is commercially available (see e.g. Sigma-Aldrich, catalogue no. 562009, CAS no. 3315-91 -1).
  • activated biphenylic compounds are biphenyl lithium, biphenyl cuprate (low and higher-order cuprates) and biphenyl zinc. Those compounds can be used individually or in the presence of another metal, e.g. copper, zinc, palladium, platinum, iron, iridium or ruthenium.
  • the biphenylic compound is a biphenylic metal reagent, preferably a biphenyl magnesium halide, especially biphenyl magnesium bromide.
  • biphenylmagnesium halide or di(biphenyl)magnesium are used.
  • initial deprotonation of the -OH group with, for example, another Grignard reagent (e.g. isopropylmagnesium chloride) or a base (e.g. sodium hydride) may be performed before addition of the activated biphenylic compound to reduce the required amount of biphenylmagnesium halide or di(biphenyl)magnesium.
  • another Grignard reagent e.g. isopropylmagnesium chloride
  • a base e.g. sodium hydride
  • 0.7 to 1 .5 equivalents preferably 1 .0 to 1 .25 equivalents are used.
  • biphenyl is preferably used as biphenylic compound.
  • the reaction is preferably carried out in the presence of a suitable Lewis acid, e.g. aluminium trichloride.
  • the biphenylic compound may be activated with a suitable functional group (for example para-silyl) to allow for milder conditions to be used during the Friedel-Crafts acylation.
  • a suitable functional group for example para-silyl
  • R2 of formula (III) is ⁇ /, ⁇ -dimethylhydroxylamino (N(Me)OMe) or morpholinyl and the biphenylic compound used is a biphenyl magnesium halide, preferably biphenyl magnesium bromide.
  • R2 of formula (III) is chloride and the biphenylic compound is biphenyl.
  • R1 is hydrogen or a nitrogen protecting group
  • R2 is a CO-activating group selected from ⁇ /, ⁇ -dimethylhydroxylamino (N(Me)OMe) and morpholinyl
  • R1 is hydrogen or a nitrogen protecting group
  • the compound of formula (III) is of formula (lll-a)
  • the reaction preferably uses a coupling agent, e.g. a diimide, such as 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC), and either ⁇ /, ⁇ - dimethylhydroxylamine or a salt therefore, or morpholine or a salt thereof, in an appropriate solvent, e.g. dichloromethane, at preferred temperatures in the range from -20 to 20 °C, e.g. from -15 to 0 °C.
  • a base e.g. an amine base, such as N- methylmorpholine
  • the carboxylic acid compound of the formula (IV) is well known in the art and the enantiomer mixture and especially the L-form are commercially available (see e.g. Sigma-Aldrich, catalogue no. 15500, CAS no. 3262-72-4).
  • the invention relates to processes using the novel compound of formula (II).
  • One aspect relates to a process for converting a compound of formula (II), or a salt thereof
  • R1 is hydrogen or a nitrogen protecting group
  • R1 is hydrogen or a nitrogen protecting group
  • the process comprising the reduction of the benzylic keto group of the compound of formula (II).
  • the compound of formula (II) is of formula (ll-a),
  • the reduction is carried out under hydrogenation conditions, preferably by using hydrogen and palladium, in particular hydrogen on charcoal.
  • the reduction of the benzylic keto group occurs preferably by hydrogenation, usually with Pd catalysts (e.g. 10% Pd/C) in an appropriate solvent, e.g. an ester, such as ethyl acetate; a ketone, such as acetone; an ether, such as methyl fe/ -butyl ether; or an aromatic solvent, such as toluene; or a mixture of one of these solvents with acetic acid, optionally in the presence of additives, e.g. sodium acetate, sodium bicarbonate, triethylamine or copper sulfate, at preferred temperatures in the range from 10 to 50 °C, e.g. from 20 to 40 °C and under preferred hydrogen pressures in the range from 1 to 20 bar, e.g. from 5 to 10 bar.
  • Pd catalysts e.g. 10% Pd/C
  • an appropriate solvent e.g. an ester, such as ethyl acetate; a
  • the Pd/C catalyst is Type 10R39 from Johnson Matthey (http://jmcct.com/products-services/product_p482.html).
  • the compound of formula (II) or formula (ll-a) is obtained by the processes described under the second aspect above, i.e. in one embodiment the present invention relates to a process for preparing a compound according to formula (I), or a salt thereof
  • R1 is hydrogen or a nitrogen protecting group, by a process comprising
  • R1 is hydrogen or a nitrogen protecting group
  • R2 is a CO-activating group, with a biphenylic compound
  • R1 is hydrogen or a nitrogen protecting group
  • the present invention relates to a process for preparing a compound according to formula (I), or a salt thereof preferably a compound of formula (l-a), or a salt thereof
  • R1 is hydrogen or a nitrogen protecting group
  • R1 is hydrogen or a nitrogen protecting group
  • R1 is hydrogen or a nitrogen protecting group
  • R2 is a CO-activating group selected from ⁇ /, ⁇ -dimethylhydroxylamino (N(Me)OMe) or morpholinyl
  • R1 is hydrogen or a nitrogen protecting group
  • R1 is hydrogen or a nitrogen protecting group
  • R1 is hydrogen or a nitrogen protecting group.
  • Such reaction of the compound of formula (I), or more specifically of formula (l-a) to the corresponding aldehyde is performed by using a TEMPO mediated oxidation (see e.g. WO 2008/031567 or WO 2014/032627, page 24-25) or using alternative reaction conditions, such as oxidation with Dess-Martin periodinane (see e.g. WO 2008/136561 ).
  • R1 in each formula where it is present is either hydrogen or a nitrogen protecting group selected from C Ce-alkyl, which is unsubstituted or mono-, di- or tri-substituted by tri-CrCe-alkylsilylCrCy-alkoxy, C 6 - C 10 -aryl, or a heterocyclic group being a mono-, bi- or tricyclic ring system with 5 to 14 ring atoms and 1 to 4 heteroatoms independently selected from N, O, S, S(O) or S(0) 2 , wherein the aryl ring or the heterocyclic group is unsubstituted or substituted by one, two or three residues, selected from the group consisting of C Cy-alkyl, hydroxyl, C Cy-alkoxy, C 2 -C 8 - alkanoyl-oxy, halogen, nitro, cyano, and CF 3 ;
  • each silyl group is a SiR1 1 R12R13 group, wherein R1 1 , R12 and R13 are, independently of each other, C Cy-alkyl, C 6 -C 10 -aryl or phenyl-C ⁇ C ⁇ alkyl.
  • R1 in each formula where it is present is the nitrogen protecting group C Cy-alkoxycarbonyl, preferably fe/ -butoxycarbonyl.
  • any of the compounds (I), (II), (III), (IV) and (V) depicted without specific configuration at the amino group carrying carbon atom can be resolved into the corresponding pure enantiomer of the formula (l-a), (ll-a), (lll-a), (IV-a) or (V-a) by using customary methods for the resolution of enantiomers from enantiomer mixtures (such as racemates), e.g. by selective crystallization (e.g. via diastereomeric salts) from solutions or emulsions or chiral chromatography. Such methods are well-known in the art.
  • One embodiment of the present invention also relates to a process for preparing NEP inhibitor prodrug /V-(3-carboxyl-1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester, or a salt thereof, comprising the manufacture of a compound of formula (I) or salt thereof, a compound of formula (II) or a salt thereof, or a compound of formula (V) or a salt thereof by any one of the processes as described in the aforementioned embodiments.
  • the synthesis of /V-(3-carboxy-1 - oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester, or a salt thereof starts from a compound of formula (l-a), or salt thereof, and a compound of formula (V-a), or a salt thereof, respectively.
  • said reaction comprises the following steps or steps in analogy thereto (see also WO 2008/031567 or WO 2014/032627, page 24-25):
  • the aldehyde of formula (V-a) is then subjected to a Wttig reaction with carbethoxyethylidene-triphenylphosphorane to deliver (R)-5-biphenyl-4- yl-4-fe/?-butoxycarbonylamino-2-methylpent-2-enoic acid ethyl ester.
  • the ester or - after saponification of the ester - the corresponding free acid (R)-5-biphenyl-4-yl-4-fe/f- butoxycarbonylamino-2-methylpent-2-enoic acid is then hydrogenated in the presence of a catalyst, whilst preferably producing the preferred diastereoisomer with high selectivity.
  • Deprotection of the nitrogen functionality, i.e. removal of the Boc group, if necessary re- introduction of the ethyl ester group, and subsequent coupling with succinic anhydride delivers the desired NEP inhibitor prodrug compound or a salt thereof.
  • the ester can be saponified to the free acid providing the NEP inhibitor drug compound.
  • the present invention relates to the use of a compound of formula (II), or a salt thereof
  • R1 is hydrogen or a nitrogen protecting group
  • Example 1 a Manufacture of (SHe/f-butyl (3-hvdroxy-1 -(methoxy(methyl)amino)-1 -oxopropan- 2-yl)carbamate 8a
  • Example 1 b Manufacture of (S)-fe/f-butyl (3-hydroxy-1 -morpholino-1 -oxopropan-2- vDcarbamate 8b
  • Example 2a Manufacture of (S)-fe/f-butyl (1 -([1 ,1 '-biphenyll-4-yl)-3-hvdroxy-1 -oxopropan-2- vDcarbamate 9 from (S)-fe/f-butyl (3-hvdroxy-1 -(methoxy(methyl)amino)-1 -oxopropan-2- vDcarbamate 8a
  • Example 2b Manufacture of (S)-fe/f-butyl (1 -([1 ,1 '-biphenyll-4-yl)-3-hydroxy-1 -oxopropan-2- vDcarbamate 9 from (S)-fe/f-butyl (3-hvdroxy-1 -morpholino-1 -oxopropan-2-yl)carbamate 8b

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  • Chemical Kinetics & Catalysis (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un nouveau procédé énantiosélectif pour produire des intermédiaires utiles pour la fabrication d'inhibiteurs NEP ou de leurs promédicaments, en particulier des inhibiteurs NEP comprenant un acide γ-amino-δ-biphenyl-α-méthylalcanoïque, ou un acide ester, un tronc.
PCT/IB2017/053971 2016-07-05 2017-06-30 Nouveau procédé pour des intermédiaires de sacubitril précoces WO2018007919A1 (fr)

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CN201780041934.1A CN109415308B (zh) 2016-07-05 2017-06-30 用于早期沙卡布曲中间体的新方法
US16/314,933 US20190256454A1 (en) 2016-07-05 2017-06-30 New process for early sacubitril intermediates
JP2018568727A JP6944473B2 (ja) 2016-07-05 2017-06-30 初期サクビトリル中間体のための新規な方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11377477B2 (en) 2018-10-12 2022-07-05 Xencor, Inc. PD-1 targeted IL-15/IL-15RALPHA fc fusion proteins and uses in combination therapies thereof
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111205204A (zh) * 2020-01-16 2020-05-29 南京红杉生物科技有限公司 沙库必曲中间体及其合成方法、应用
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Citations (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2516098A (en) * 1949-03-26 1950-07-25 Parke Davis & Co Biphenyl compounds
US5217996A (en) 1992-01-22 1993-06-08 Ciba-Geigy Corporation Biaryl substituted 4-amino-butyric acid amides
WO2007056546A1 (fr) 2005-11-09 2007-05-18 Novartis Ag Combinaison pharmaceutiques d'un antagoniste de recepteur d'angiotensine et d'un inhibiteur de nep
WO2007083776A1 (fr) 2006-01-17 2007-07-26 Sumitomo Chemical Company, Limited Procédé de production d'un composé de biphénylalanine optiquement actif ou d'un de ses sels ou esters
WO2007083774A1 (fr) 2006-01-17 2007-07-26 Sumitomo Chemical Company, Limited Biphénylméthylhydantoïne, méthode de synthèse dudit composé et méthode de synthèse de biphénylalanine utilisant ledit composé
WO2008031567A1 (fr) 2006-09-13 2008-03-20 Novartis Ag Procédé de préparation d'acide 4-amino-butyrique substitué par biaryle ou de dérivés de celui-ci et leur utilisation pour produire des inhibiteurs de nep
WO2008083967A2 (fr) 2007-01-12 2008-07-17 Novartis Ag Nouveau procédé
WO2008120567A1 (fr) 2007-03-20 2008-10-09 Sumitomo Chemical Company, Limited Procédé de recueil du sel du composé l-biphénylalanine et procédé de recueil de composé d'ester de biphénylalanine utilisant celui-ci
WO2008136561A1 (fr) 2007-05-03 2008-11-13 Ls Mtron, Ltd. Matériau d'anode d'une batterie secondaire et batterie secondaire utilisant celui-ci
WO2009090251A2 (fr) 2008-01-17 2009-07-23 Novartis Ag Nouveaux procédés
WO2010081410A1 (fr) 2009-01-13 2010-07-22 Zhejiang Jiuzhou Pharmaceutical Co., Ltd. Procédé de fabrication et de dédoublement de l'acide 2-acylamino-3-diphénylpropanoïque
WO2011035569A1 (fr) 2009-09-23 2011-03-31 Zhejiang Jiuzhou Pharmaceutical Co., Ltd. Procédé pour la fabrication de n-acylbphénylalanine
WO2011088797A1 (fr) 2010-01-22 2011-07-28 Novartis Ag Intermédiaires de l'endopeptidase neutre et leur procédé de préparation
CN102260177A (zh) 2010-05-25 2011-11-30 中国医学科学院药物研究所 丙二醇类衍生物、其制备方法和其药物组合物与用途
WO2012025502A1 (fr) 2010-08-23 2012-03-01 Novartis Ag Nouveau procédé de préparation d'intermédiaires utilisés pour produire des inhibiteurs de l'endopeptidase neutre (epn)
WO2012025501A1 (fr) 2010-08-23 2012-03-01 Novartis Ag Procédé de préparation d'intermédiaires pour produire des inhibiteurs de l'endopeptidase neutre (epn)
WO2013026773A1 (fr) 2011-08-19 2013-02-28 Dsm Ip Assets B.V. Synthèse de r-biphénylalaninol
CN103483201A (zh) 2013-09-12 2014-01-01 江苏弘和药物研发有限公司 一种(r)-2-甲基-4-硝基-1-丁醇的合成方法
WO2014032627A1 (fr) 2012-08-31 2014-03-06 Zhejiang Jiuzhou Pharmaceutical Co., Ltd Nouveau procédé
WO2015024991A1 (fr) 2013-08-21 2015-02-26 Dpx Holdings B.V. Synthèse de biphénylalaninol à l'aide de nouveaux intermédiaires
CN104557600A (zh) 2015-01-26 2015-04-29 苏州明锐医药科技有限公司 沙库比曲的制备方法
CN104725279A (zh) 2015-02-12 2015-06-24 威海迪素制药有限公司 一种N-Boc-联苯丙氨酸衍生物的制备方法
CN104725256A (zh) 2015-02-11 2015-06-24 威海迪素制药有限公司 一种联苯丙氨酸衍生物的制备方法
CN105017082A (zh) 2015-07-31 2015-11-04 上海皓元化学科技有限公司 一种心衰药Entresto 关键中间体(R)-叔丁基 (1-([1,1`-联苯]-4-基)-3-羟基丙烷-2-基)氨基甲酸酯的制备方法
CN105061263A (zh) 2015-08-11 2015-11-18 苏州楚凯药业有限公司 一种nep抑制剂中间体的制备方法
CN105085322A (zh) 2015-08-15 2015-11-25 浙江永宁药业股份有限公司 Ahu-377中间体的制备方法及其中间体和中间体的制备方法
CN105152980A (zh) 2015-09-11 2015-12-16 浙江永宁药业股份有限公司 N-叔丁氧羰基-（4s）-（对苯基苯基甲基）-4-氨基-（2r）-甲基丁酸的手性制备方法
CN105168205A (zh) 2015-08-18 2015-12-23 泰力特医药（湖北）有限公司 一种血管紧张素ii受体和脑啡肽酶受体双重抑制剂lcz696的制备方法
CN105198775A (zh) 2015-10-10 2015-12-30 凯瑞斯德生化(苏州)有限公司 一种手性N-Boc联苯丙氨醇的制备方法
CN105237560A (zh) 2015-10-15 2016-01-13 上海博氏医药科技有限公司 一种lzc696中间体及其合成方法
CN105330569A (zh) 2015-09-11 2016-02-17 天台宜生生化科技有限公司 一种(r)-2-(n-叔丁氧羰基氨基)联苯丙醇的制备方法
CN105481622A (zh) 2015-12-14 2016-04-13 武汉凯特立斯科技有限公司 一种α-氧代-α,β-不饱和羧酸的不对称氢化方法
CN105566194A (zh) 2016-02-01 2016-05-11 张伯引 一种Sacubitril中间体的制备方法
CN105601524A (zh) 2016-03-17 2016-05-25 海门慧聚药业有限公司 Lcz696关键中间体的制备

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2543267A (en) * 1950-01-04 1951-02-27 Parke Davis & Co Hydroxyethyl-acylamidobiphenylyl ketones
AR227636A1 (es) * 1978-11-25 1982-11-30 Nippon Kayaku Kk Procedimiento para producir acido treo-3-amino-2-hidroxibutanoil aminoacetico intermediarios para prepararlo y procedimiento para preparar los intermediarios
JPS5690050A (en) * 1979-11-20 1981-07-21 Microbial Chem Res Found Novel threo-3-amino-2-hydroxybutanoylaminoacetic acid
WO2005042481A2 (fr) * 2003-10-30 2005-05-12 Northwestern University Composes et procedes associes pour une reactivation de p53 mutante
WO2017203474A1 (fr) * 2016-05-27 2017-11-30 Dr. Reddy's Laboratories Limited Procédé de préparation d'intermédiaire de sacubutril

Patent Citations (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2516098A (en) * 1949-03-26 1950-07-25 Parke Davis & Co Biphenyl compounds
US5217996A (en) 1992-01-22 1993-06-08 Ciba-Geigy Corporation Biaryl substituted 4-amino-butyric acid amides
WO2007056546A1 (fr) 2005-11-09 2007-05-18 Novartis Ag Combinaison pharmaceutiques d'un antagoniste de recepteur d'angiotensine et d'un inhibiteur de nep
WO2007083776A1 (fr) 2006-01-17 2007-07-26 Sumitomo Chemical Company, Limited Procédé de production d'un composé de biphénylalanine optiquement actif ou d'un de ses sels ou esters
WO2007083774A1 (fr) 2006-01-17 2007-07-26 Sumitomo Chemical Company, Limited Biphénylméthylhydantoïne, méthode de synthèse dudit composé et méthode de synthèse de biphénylalanine utilisant ledit composé
WO2008031567A1 (fr) 2006-09-13 2008-03-20 Novartis Ag Procédé de préparation d'acide 4-amino-butyrique substitué par biaryle ou de dérivés de celui-ci et leur utilisation pour produire des inhibiteurs de nep
WO2008083967A2 (fr) 2007-01-12 2008-07-17 Novartis Ag Nouveau procédé
WO2008120567A1 (fr) 2007-03-20 2008-10-09 Sumitomo Chemical Company, Limited Procédé de recueil du sel du composé l-biphénylalanine et procédé de recueil de composé d'ester de biphénylalanine utilisant celui-ci
WO2008136561A1 (fr) 2007-05-03 2008-11-13 Ls Mtron, Ltd. Matériau d'anode d'une batterie secondaire et batterie secondaire utilisant celui-ci
WO2009090251A2 (fr) 2008-01-17 2009-07-23 Novartis Ag Nouveaux procédés
WO2010081410A1 (fr) 2009-01-13 2010-07-22 Zhejiang Jiuzhou Pharmaceutical Co., Ltd. Procédé de fabrication et de dédoublement de l'acide 2-acylamino-3-diphénylpropanoïque
WO2011035569A1 (fr) 2009-09-23 2011-03-31 Zhejiang Jiuzhou Pharmaceutical Co., Ltd. Procédé pour la fabrication de n-acylbphénylalanine
WO2011088797A1 (fr) 2010-01-22 2011-07-28 Novartis Ag Intermédiaires de l'endopeptidase neutre et leur procédé de préparation
CN102260177A (zh) 2010-05-25 2011-11-30 中国医学科学院药物研究所 丙二醇类衍生物、其制备方法和其药物组合物与用途
WO2012025502A1 (fr) 2010-08-23 2012-03-01 Novartis Ag Nouveau procédé de préparation d'intermédiaires utilisés pour produire des inhibiteurs de l'endopeptidase neutre (epn)
WO2012025501A1 (fr) 2010-08-23 2012-03-01 Novartis Ag Procédé de préparation d'intermédiaires pour produire des inhibiteurs de l'endopeptidase neutre (epn)
WO2013026773A1 (fr) 2011-08-19 2013-02-28 Dsm Ip Assets B.V. Synthèse de r-biphénylalaninol
WO2014032627A1 (fr) 2012-08-31 2014-03-06 Zhejiang Jiuzhou Pharmaceutical Co., Ltd Nouveau procédé
WO2015024991A1 (fr) 2013-08-21 2015-02-26 Dpx Holdings B.V. Synthèse de biphénylalaninol à l'aide de nouveaux intermédiaires
CN103483201A (zh) 2013-09-12 2014-01-01 江苏弘和药物研发有限公司 一种(r)-2-甲基-4-硝基-1-丁醇的合成方法
CN104557600A (zh) 2015-01-26 2015-04-29 苏州明锐医药科技有限公司 沙库比曲的制备方法
CN104725256A (zh) 2015-02-11 2015-06-24 威海迪素制药有限公司 一种联苯丙氨酸衍生物的制备方法
CN104725279A (zh) 2015-02-12 2015-06-24 威海迪素制药有限公司 一种N-Boc-联苯丙氨酸衍生物的制备方法
CN105017082A (zh) 2015-07-31 2015-11-04 上海皓元化学科技有限公司 一种心衰药Entresto 关键中间体(R)-叔丁基 (1-([1,1`-联苯]-4-基)-3-羟基丙烷-2-基)氨基甲酸酯的制备方法
CN105061263A (zh) 2015-08-11 2015-11-18 苏州楚凯药业有限公司 一种nep抑制剂中间体的制备方法
CN105085322A (zh) 2015-08-15 2015-11-25 浙江永宁药业股份有限公司 Ahu-377中间体的制备方法及其中间体和中间体的制备方法
CN105168205A (zh) 2015-08-18 2015-12-23 泰力特医药（湖北）有限公司 一种血管紧张素ii受体和脑啡肽酶受体双重抑制剂lcz696的制备方法
CN105152980A (zh) 2015-09-11 2015-12-16 浙江永宁药业股份有限公司 N-叔丁氧羰基-（4s）-（对苯基苯基甲基）-4-氨基-（2r）-甲基丁酸的手性制备方法
CN105330569A (zh) 2015-09-11 2016-02-17 天台宜生生化科技有限公司 一种(r)-2-(n-叔丁氧羰基氨基)联苯丙醇的制备方法
CN105198775A (zh) 2015-10-10 2015-12-30 凯瑞斯德生化(苏州)有限公司 一种手性N-Boc联苯丙氨醇的制备方法
CN105237560A (zh) 2015-10-15 2016-01-13 上海博氏医药科技有限公司 一种lzc696中间体及其合成方法
CN105481622A (zh) 2015-12-14 2016-04-13 武汉凯特立斯科技有限公司 一种α-氧代-α,β-不饱和羧酸的不对称氢化方法
CN105566194A (zh) 2016-02-01 2016-05-11 张伯引 一种Sacubitril中间体的制备方法
CN105601524A (zh) 2016-03-17 2016-05-25 海门慧聚药业有限公司 Lcz696关键中间体的制备

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
"Bioreversible Carriers in Drug Design", 1987, AMERICAN PHARMACEUTICAL ASSOCIATION AND PERGAMON PRESS
"Design of Prodrugs", 1985, ELSEVIER
"Methoden der organischen Chemie", vol. 15/1, 1974, GEORG THIEME VERLAG, article "Methods of Organic Chemistry"
"The Peptides", vol. 3, 1981, ACADEMIC PRESS
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 3262-72-4
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 3315-91-1
J. AM. CHEM. SOC., vol. 103, 1981, pages 6157
J. F. W. MCOMIE: "Protective Groups in Organic Chemistry", 1973, PLENUM PRESS
JUDKINS ET AL., SYNTHETIC COMMUNICATIONS, vol. 26, 1996, pages 4351 - 4367
KSANDER ET AL., J. MED. CHEM., vol. 38, 1995, pages 1689 - 1700
P. G. M. WUTS; T. W. GREENE: "Greene's Protective Groups in Organic Synthesis", 2007, WILEY
R. B. SILVERMAN: "The Organic Chemistry of Drug Design and Drug Action", 2004, ELSEVIER ACADEMIC PRESS, pages: 497 - 557
T. HIGUCHI; V. STELLA: "Pro-drugs as Novel Delivery Systems", ACS SYMPOSIUM SERIES, vol. 14

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11584794B2 (en) 2016-10-14 2023-02-21 Xencor, Inc. Bispecific heterodimeric fusion proteins containing IL-15-IL-15Ralpha Fc-fusion proteins and immune checkpoint antibody fragments
US11505595B2 (en) 2018-04-18 2022-11-22 Xencor, Inc. TIM-3 targeted heterodimeric fusion proteins containing IL-15/IL-15RA Fc-fusion proteins and TIM-3 antigen binding domains
US11524991B2 (en) 2018-04-18 2022-12-13 Xencor, Inc. PD-1 targeted heterodimeric fusion proteins containing IL-15/IL-15Ra Fc-fusion proteins and PD-1 antigen binding domains and uses thereof
US11377477B2 (en) 2018-10-12 2022-07-05 Xencor, Inc. PD-1 targeted IL-15/IL-15RALPHA fc fusion proteins and uses in combination therapies thereof
US11618776B2 (en) 2018-12-20 2023-04-04 Xencor, Inc. Targeted heterodimeric Fc fusion proteins containing IL-15/IL-15RA and NKG2D antigen binding domains
US11932675B2 (en) 2019-10-11 2024-03-19 Genentech, Inc. PD-1 targeted IL-15/IL-15Rα Fc fusion proteins with improved properties

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